Process for preparing tetracyclic amines useful as cerebrovascular agents

ABSTRACT

Processes for the preparation of a series of tetracyclic amines useful in the treatment and/or prevention of cerebrovascular disorders are disclosed.

This is a divisional application of U.S. Ser. No. 07/677,029 filed Mar.28, 1991, now U.S. Pat. No. 5,070,093, which is a divisional applicationof U.S. Ser. No. 07/565,306 filed Aug. 9, 1990, now U.S. Pat. No.5,109,136.

BACKGROUND OF THE INVENTION

Excessive excitation by neurotransmitters can cause the degeneration anddeath of neurons. It is believed that this degeneration is in partmediated by the excitotoxic actions of glutamate and aspartate at theN-methyl-D-aspartate (NMDA) receptor. This excitotoxic action isresponsible for the loss of neurons in cerebrovascular disorders suchas: cerebral ischemia or cerebral infraction resulting from a range ofconditions such as thromboembolic or hemorrhagic stroke, cerebralvasospasm, hypoglycemia, cardiac arrest, status epilepticus, perinatalasphyxia, cerebral trauma and anoxia (such as from drowning andpulmonary surgery).

There are no specific therapies for these neurodegenerative diseases,however, compounds which act specifically as antagonists of the NMDAreceptor complex, either competitively or noncompetitively, offer anovel therapeutic approach to these disorders: R. Schwarcz and B.Meldrum, The Lancet 140 (1985); B. Meldrum in "Neurotoxins and TheirPharmacological Implications" edited by P. Jenner, Raven Press, New York(1987); D. W. Choi, Neuron 1:623 (1988). Confirmation of the protectiveeffects of noncompetitve NMDA antagonists in various pharmacologicalmodels of neurodegenerative disorders have appeared in the literature:J. W. McDonald, F. S. Silverstein, and M. V. Johnston, Eur. J.Pharmocol. 140:359 (1987); R. Gill, A. C. Foster, and G. N. Woodruff, J.Neurosci. 7:3343 (1987); S. M. Rothman, J. H. Thurston, R. E. Hauhart,G. D. Clark, and J. S. Soloman, Neurosci. 21:673 (1987); M. P. Goldbert,P-C. Pham, and D. W. Choi, Neurosci. Lett. 80:11 (1987); L. F. Copeland,P. A. Boxer, and F. W. Marcoux, Soc. Neurosci. Abstr. 14 (part 1):420(1988); J. A. Kemp, A. C. Foster, R. Gill, and G. N. Woodruff, TIPS8:414 (1987); R. Gill, A. C. Foster, and G. N. Woodruff, J. Neurosci.25:847 (1988); C. K. Park, D. G. Nehls, D. I. Graham, G. M. Teasdale,and J. M. McCulloch, Ann. Neurol. 24:543 (1988); G. K. Steinburg, C. P.George, R. DeLaPlaz, D. K. Shibata, and T. Gross, Stroke 19:1112 (1988);J. F. Church, S. Zeman, and D. Lodge, Anesthesiology 69:702 (1988).

The compounds of the present invention are useful in the treatment ofneurodegenerative disorders including cerebrovascular disorders. Suchdisorders include but are not limited to cerebral ischemia or cerebralinfarction resulting from a range of conditions such as thromboembolicor hemorrhagic stroke, cerebral vasospasm, hypoglycemia, cardiac arrest,status epilepticus, perinatal asphyxia, cerebral trauma and anoxia suchas from drowning and/or pulmonary surgery. Other treatments are forschizophrenia, epilepsy, spasticity, neurodegenerative disorders such asAlzheimer's disease or Huntington's disease, Olivo-pontocerebellaratrophy, spinal cord injury, and poisoning by exogenous NMDA poisons(e.g., some forms of lathyrism). Further uses are as analgesics andanesthetics, particularly for use in surgical procedures where a finiterisk of cerebrovascular damage exists.

SUMMARY OF THE INVENTION

The present invention concerns compounds of the formula I ##STR1## or apharmaceutically acceptable acid addition salt thereof wherein R¹, R²,R³, m, and n are as described herein below.

The present invention also includes a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of formula Itogether with a pharmaceutically acceptable carrier.

The present invention also includes a method for treatingcerebrovascular disorders which comprises administering to a patient inneed thereof the above pharmaceutical composition in unit dosage form.

The present invention also includes a method of treating disordersresponsive to the blockade of glutamic and aspartic acid receptors in apatient comprising administering a therapeutically effective amount ofthe above composition.

The invention also includes a method for treating cerebral ischemia,cerebral infarction, cerebral vasospasm, hypoglycemia, cardiac arrest,status epilepticus, cerebral trauma, schizophrenia, epilepsy,neurodegenerative disorders, Alzheimer's disease, or Huntington'sdisease comprising administering to a patient in need thereof atherapeutically effective amount of the above composition.

The invention also includes a method for treating stroke in patients inneed thereof which comprises administering to a patient in need thereofa therapeutically effective amount of the above composition.

The invention also includes using as an anesthetic the above compositionin surgical operations where a risk of cerebrovascular damage exists.

The invention further includes processes for the preparation ofcompounds of formula I.

The invention still further includes novel intermediates useful in theprocesses.

DETAILED DESCRIPTION

The present invention concerns compounds of the formula ##STR2## or apharmaceutically acceptable acid addition salt thereof wherein: R¹ ishydrogen, lower alkyl, lower alkenyl, lower alkynyl, arylloweralkyl,cyclopropylloweralkyl, or a pharmaceutically acceptable labile group;

R² and R³ are each independently hydrogen, lower alkyl, hydroxy, loweralkoxy, halogen, amino, monoloweralkylamino, diloweralkylamino;

m is an integer of from 0 to 2; and

n is an integer of from 2 to 4.

Preferred compounds of the instant invention are those of formula Iwherein:

R¹ is hydrogen, lower alkyl, lower alkenyl, cyclopropylmethyl orarylloweralkyl;

R² and R³ are independently hydrogen, lower alkyl, hydroxy, or loweralkoxy;

m is an integer of 0 or 1;

n is 2 or 3; and

indicates the ring is cis relative to its attachment to the molecule.

More preferred compounds of the instant invention are those of formula Iwherein:

R¹ is hydrogen, lower alkyl, cyclopropylmethyl, or arylloweralkyl;

R² and R³ are independently hydrogen, hydroxy, or lower alkoxy;

m is an integer 0 or 1; and

n is an integer 2 or 3.

Still more preferred are compounds of formula I wherein:

R¹ is hydrogen, methyl, ethyl, propyl, allyl, cyclopropylmethyl, orbenzyl;

R² and R³ are each independently hydrogen, methoxy, or hydroxy;

m is the integer 0 or 1; and

n is the integer 2 or 3.

Other more preferred compounds of the instant invention include:

(+), (-), or (+/-)-2,3-Dihydro-1H,4H-3a,8b-butanoindeno[1,2-b]pyrrole,

(+), (-), or(+/-)-2,3-Dihydro-7-methoxy-1H,4H-3a,8b-butanoindeno[1,2-b]pyrrole,

(+), (-), or(+/-)-2,3-Dihydro-1-methyl-1H,4H-3a,8b-butanoindeno[1,2-b]pyrrole,

(+), (-), or(+/-)-2,3-Dihydro-7-methoxy-1-methyl-1H,4H-3a,8b-butanoindeno[1,2-b]pyrrole,

(+), (-) or(+/-)-2,3-Dihydro-7-methoxy-1-ethyl-1H,4H-3a,8b-butanoindeno[1,2-b]pyrrole

(+), (-), or(+/-)-2,3,4,5-tetrahydro-1-(2-propenyl)-3a,9b-butano-1H-benz[g]indole,

(+), (-), or (+/-)-2,3,4,5-Tetrahydro-3a,9b-butano-1H-benz[g]indol-8-ol,

(+), (-), or(+/-)-2,3,4,5-Tetrahydro-1-methyl-3a,9b-butano-1H-benz[g]indol-8-ol,

(+), (-), or(+/-)-2,3-Dihydro-1H,4H-3a,8b-butanoindeno[1,2-b]pyrrol-7-ol,

(+), (-), or(+/-)-2,3-Dihydro-1-methyl-1H,4H-3a,8b-butanoindeno[1,2-b]pyrrol-7-ol,

(+), (-), or (+/-)-1,2,3,4,5,6-Hexahydro-4a,10b-butanobenz[h]quinoline,

(+), (-), or(+/-)-1,2,3,4,5,6-Hexahydro-9-methoxy-4a,10b-butanobenz[h]quinoline,

(+), (-), or(+/-)-1,2,3,4,-Tetrahydro-4a,9b-butano-5H-indeno[1,2-b]pyridine,

(+), (-), or(+/-)-1,2,3,4,-Tetrahydro-8-methoxy-4a,9b-butano-5H-indeno[1,2-b]pyridine,

(+), (-), or (+/-)-1,2,3,4,5,6-Hexahydro-1-methyl-4a,10b-butanobenz[h]quinoline,

(+), (-), or(+/-)-1,2,3,4,5,6-Hexahydro-9-methoxy-1-methyl-4a,10b-butanobenz[h]quinoline,

(+), (-), or(+/-)-1,2,3,4,-Tetrahydro-1-methyl-4a,9b-butano-5H-indeno[1,2-b]pyridine,

(+), (-), or(+/-)-1,2,3,4,-Tetrahydro-8-methoxy-1-methyl-4a,9b-butano-5H-indeno[1,2-b]pyridine,

(+), (-), or(+/-)-1,2,3,4,5,6-Hexahydro-4a,10b-butanobenz[h]quinolin-9-ol,

(+), (-), or(+/-)-1,2,3,4,5,6-Hexahydro-1-methyl-4a,10b-butanobenz[h]quinolin-9-ol,

(+), (-), or(+/-)-1,2,3,4-Tetrahydro-4a,9b-butano-5H-indeno[1,2-b]pyridin-8-ol, and

(+), (-), or(+/-)-1,2,3,4-Tetrahydro-1-methyl-4a,9b-butano-5H-indeno[1,2-b]pyridin-8-ol.

Most preferred compounds of the instant invention are:

(+), (-), or (+/-)-2,3,4,5-Tetrahydro-3a,9b-butano-1H-benz[g]indole,

(+), (-), or(+/-)-2,3,4,5-Tetrahydro-1-methyl-3a,9b-butano-1H-benz[g]indole,

(+), (-), or(+/-)-2,3,4,5-Tetrahydro-1-ethyl-3a,9b-butano-1H-benz[g]indole,

(+), (-), or(+/-)-2,3,4,5-Tetrahydro-1-propyl-3a,9b-butano-1H-benz[g]indole,

(+), (-), or(+/--)-2,3,4,5-Tetrahydro-1-(cyclopropylmethyl)-3a,9b-butano-1H-benz[g]indole,

(+), (-), or(+/-)-2,3,4,5-Tetrahydro-1-phenylmethyl-3a,9b-butano-1H-benz[g]indole,

(+), (-), or(+/--)-2,3,4,5-Tetrahydro-8-methoxy-3a,9b-butano-1H-benz[g]indole,

(+), (-), or(+/-)-2,3,4,5-Tetrahydro-8-methoxy-1-ethyl-3a,9b-butano-1H-benz[g]indole,and

(+), (-), or(+/-)-2,3,4,5-Tetrahydro-8-methoxy-1-ethyl-3a,9b-butano-1H-benz[g]indole.

Compounds of the instant invention include solvates, hydrates, andpharmaceutically acceptable salts of compounds of formula I above.

The compounds of the present invention contain asymmetric carbon atoms.The instant invention includes the individual enantiomers, which may beprepared or isolated by methods known in the art.

Any resulting racemates can be resolved into the optical antipodes byknown methods, for example by separation of the diastereomeric saltsthereof, with an optically active acid, and liberating the opticallyactive amine compound by treatment with a base. Racemic compounds of theinstant invention can thus be resolved into their optical antipodese.g., by fractional crystallization of d- or 1- (tartarates, mandelates,or camphorsulfonate) salts. The compounds of the instant invention mayalso be resolved into the optical antipodes by the formation ofdiastereomeric carbamates by reacting the compounds of the instantinvention with an optically active chloroformate, for example(-)-menthyl chloroformate, or by the formation of a diastereomeric amideby reacting the compounds of the instant invention with an opticallyactive activated carboxy acid such as that derived from (+) or (-)phenylalanine, (+) or (-) phenylglycine, (-)-camphanic acid or the like.

Additional methods for resolving optical isomers, known to those skilledin the art may be used, for example those discussed by J. Jaques, A.Collet, and S. Wilen in "Enantiomers, Racemates and Resolutions", JohnWiley and Sons, New York (1981).

The term lower in connection with organic groups, radical or compoundsincludes up to and including seven members, preferably up to andincluding four and most preferably one, two, or three carbon atomsexcept as otherwise specifically described.

Lower alkyl means a straight or branched chain of from one to fourcarbon atoms including but not limited to methyl, ethyl, propyl,isopropyl, and butyl.

Lower alkenyl means a group from one to four carbon atoms, for example,but not limited to ethylene, 1,2- or 2,3-propylene, 1,2- 2,3-, or3,4butylene. Preferred is 2,3-propylene.

Lower alkynyl means a group from one to four carbon atoms, for example,but not limited to ethynyl, 2,3-propynyl, 2,3-, or 3,4-butynyl; propynylis the preferred group.

Cyclopropylloweralkyl means cyclopropyl-C₁₋₄ -alkyl, meaning forexample, cyclopropylmethyl, 2-(cyclopropyl)ethyl, 3-(cyclopropyl)propyl;cyclopropylmethyl is the preferred group.

Lower alkoxy means a group of from one to four carbon atoms, forexample, but not limited to methoxy, ethoxy, propoxy; methoxy is thepreferred group.

Halogen is fluorine, chlorine, bromine, or iodine; fluorine, chlorine,and bromine are the preferred groups.

Arylloweralkyl means aryl-C₁₋₄ -alkyl, meaning for example, benzyl,2-phenylethyl, 3-phenylpropyl; preferred group is benzyl. The arylgroups may be substituted, for example, by lower alkyl, lower alkoxy,hydroxy, and halogen.

Monoloweralkylamino means a group containing from one to four carbonatoms, for example, but not limited to methylamino, ethylamino, n- ori-(propylamino or butylamino).

Diloweralkylamino means a group containing from one to four carbon atomsin each lower alkyl group, for example, but not limited todimethylamino, diethylamino, di-(n-propyl)-amino, di-(n-butyl)-amino, ormay represent a fused ring, for example piperidine.

Physiologically labile group includes but is not limited to suchderivatives described by; I. H. Pitman in Med. Chem. Rev. 2:189 (1981);J. Alexander, R. Cargill, S. R. Michelson and H. Schwam in J. Med. Chem.31:318 (1988); V. H. Naringrekar and V. J. Stella in European PatentApplication 214,009-A2 and include certain amides, such as amides ofamino acids, for example glycine, or serine, enaminone derivatives and(acyloxy)alkylcarbamates.

Well-known protecting groups and their introduction and removal aredescribed, for example, in J. F. W. McOmie, Protective Groups in OrganicChemistry, Plenum Press, London, New York (1973), and T. W. Greene,Protective Groups in Organic Synthesis, Wiley, New York (1981).

Salts of the compounds of the invention are preferably pharmaceuticallyacceptable salts. The compounds of the invention are basic amines fromwhich acid addition salts of pharmaceutically acceptable inorganic ororganic acids such as strong mineral acids, for example, hydrohalic,e.g., hydrochloric or hydrobromic acid; sulfuric, phosphoric or nitricacid; aliphatic or aromatic carboxylic or sulfonic acids, e.g., acetic,propionic, succinic, glycolic, lactic, malic, tartaric, gluconic,citric, ascorbic, maleic, fumaric, pyruvic, pamoic, nicotinic,methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, benzenesulfonic,p-toluenesulfonic, or napthlenesulfonic acid can be prepared.

For isolation or purification purposes, salts may be obtained whichmight not be useful for pharmaceutical purposes. Pharmaceuticallyacceptable salts useful for therapeutic purposes are preferred.

The present invention also includes processes for making the compoundsof formula I above.

One process for the preparation of compounds of formula I is illustratedin Scheme A below. ##STR3##

Step (1) The compound of formula II where m is 0 or 1 ##STR4## and R²and R³ are as previously defined are treated with 1,4-dibromobutaneunder conditions described in Bull. Soc. Chim. France 346 (1957) to givethe compounds of the formula III. ##STR5##

Step (2) The compounds of the formula III are treated withlithioacetonitrile, in a solvent such as ether, tetrahydrofuran, or thelike, at a temperature between -78° C. and 20° C. to afford thecompounds of the formula IV. ##STR6##

Step (3) The compounds of the formula IV are hydrogenated in thepresence of a catalyst such as Raney Nickel, or the like, in a solventsuch as methanol or ethanol containing ammonia, under a hydrogenatmosphere to give the compounds of the formula V where n is 2. ##STR7##

Step (4) Alternatively, the compounds of the formula III are treatedwith a compound of the formula VI ##STR8## under conditions described byEvans et al in J. Amer. Chem. Soc. 371, (1979) or by other methods knownto those skilled in the art, such as those described in Tetrahedron 205,(1983) to give the compounds of the formula VII. ##STR9##

Step (5) The compounds of the formula VII are treated with ammonia in asolvent such as toluene, tetrahydrofuran, or the like to give thecompounds of the formula VIII. ##STR10##

Step (6) The compounds of the formula VIII are reduced using lithiumaluminum hydride, diborane, or the like, in a solvent such as ether,tetrahydrofuran, or the like to give the compounds of the formula Vwherein n is 3.

Step (7) The compounds of the formula V are treated with methylchloroformate, ethyl chloroformate, 2,2,2-trichloroethyl chloroformateor an optically active chloroformate, for example (-)-menthylchloroformate, (-)-α-methylbenzyl chloroformate or the like, in thepresence of a trialkylamine such as triethylamine, tributylamine,diisopropylethylamine or the like, in a solvent such as dichloromethane,chloroform, or the like, to give the compounds of the formula IX whereinR⁵ is methyl, ethyl, 2,2,2-trichloroethyl, (-)-menthol,(-)-α-methylbenzyl, or other acid stable protecting group. ##STR11##

Step (8) The compounds of the formula IX are treated with acetic acid,formic acid, triflouroacetic acid, sulfuric acid or the like orcombinations thereof, preferably combinations of acetic acid andsulfuric acid to give the compounds of the formula X ##STR12##

Step (9) The compounds of the formula X are treated to remove thecarbamate functionalitity using methods known to those skilled in theart for example wherein R⁵ is 2,2,2-trichloroethyl the compounds aretreated with zinc dust in methanol, ethanol or the like, in the presenceof acetic acid, to afford the compounds of the formula I wherein n is 2or 3, m is 0 or 1, R¹ is hydrogen and R² and R³ are as previouslydefined.

Step (10) The compounds of the formula I wherein R¹ is hydrogen aretreated with an aldehyde such as R formaldehyde, acetaldehyde,benzaldehyde or the like or with a ketone such as acetone, acetophenone,or the like, in the presence of a reducing agent such as sodiumcyanoborohydride or the like, in a solvent such as methanol, ethanol orthe like to give the compounds of the formula I wherein n is 2 or 3, mis 0 or 1, R¹ is as previously defined excepting hydrogen, and R² and R³are as previously defined.

Step (11) Alternatively the compounds of the formula X are reduced inthe presence of lithium aluminum hydride, diborane or the like, in asolvent such as ether, tetrahydrofuran or the like, to afford thecompound of the formula I wherein R¹ is methyl.

Novel intermediates useful in the preparation of compounds of formula Iare:

Spiro[cyclopentane-1,1'-[1H]inden]-2'(3'H)-one,7'-methoxy-spiro[cyclopentane-1,1'-[1H]inden]-2'(3'H)-one,

(+), (-), or(+/-)-3',4,-Dihydro-2'-hydroxyspiro[cyclopentane-1,1'(2'H)-napthalen]-2'-acetonitrile,

(+), (-), or(+/-)-3',4,-dihydro-2'-hydroxy-7'-methoxyspiro[cyclopentane-1,1'(2'H)-napthalen]-2'acetonitrile,

(+), (-), or(+/-)-2',3'-Dihydro-2'-hydroxyspiro[cyclopentane-1,1'-[1H]inden]-2'-acetonitrile,

(+), (-), or(+/-)-2',3'-Dihydro-2'-hydroxy-6-methoxyspiro[cyclopentane-1,1'-[1H]inden]-2'acetonitrile,

(+), (-), or(+/-)-2'-(2-aminoethyl)-3',4'-dihydrospiro[cyclopentane-1,1'(2H)-napthalen]-2'-ol,

(+), (-), or(+/-)-2'-(2-aminoethyl)-3',4'-dihydro-7'-methoxyspiro[cyclopentane-1,1'(2'H)-napthalen]-2'-ol,

(+), (-), or(+/-)-2'-(2-aminoethyl)-2',3'dihydrospiro[cyclopentane-1,1'-[1H]inden-2'-ol,

(+), (-), or(+/-)-2'-(2-aminoethyl)-2',3'-dihydro-6'-methoxyspiro[cyclopentane-1,1'-[1H]inden-2'-ol,

Ethyl (+), (-), or(+/-)-[2-(3',4'-dihydro-2'-hydroxyspiro[cyclopentane-1,1'(2'H)-napthalen]-2'yl)ethyl]carbamate,

(+), (-), or(+/-)-2,2,2-Trichloroethyl-[2-(3',4'-dihydro-2'-hydroxyspiro[cyclopentane-1,1'(2,H)-naphthalen]2'-yl)ethyl]carbamate,

(+), (-), or(+/-)-2,2,2-Trichloroethyl-[2-(3',4'-dihydro-2'-hydroxy-7'-methoxyspiro[cyclopentane-1,1'(2'H)-naphthalen]-2'-yl)ethyl]carbamate,

(+), (-), or(+/-)-2,2,2-Trichloroethyl-[2-[2',3'-dihydro-2'-hydroxyspiro[cyclopentane-1,1'-[1H]inden]2'-yl)ethyl]carbamate,

(+), (-), or(+/-)-2,2,2-Trichloroethyl-[2-[2',3'-dihydro-2'-hydroxy-6'-methoxyspiro[cyclopentane-1,1'-[1H]inden]-2'-yl)ethyl)carbamate,

Ethyl (+), (-), or(+/-)-2,3,4,5-tetrahydro-3a,9b-butano-1H-benz[g]indole-1-carboxylate,

(+), (-), or(+/-)-2,2,2-Trichloroethyl-2,3,4,5-tetrahydro-3a,9b-butano-1H-benz[g]indole-1-carboxylate,

(+), (-), or(+/-)-2,2,2-Trichloroethyl-2,3,4,5-tetrahydro-8-methoxy-3a,9b-butano-1H-benz[g]indole-1-carboxylate,

(+), (-), or(+/-)-2,2,2-Trichloroethyl-2,3-dihydro-1H,4H-3a,8b-butanoindeno[1,2-b]pyrrole-1-carboxylate,

(+), (-), or(+/-)-2,2,2-Trichloroethyl-2,3-dihydro-7-methoxy-1H,4H-3a,8b-butanoindeno[1,2-b]pyrrole-1-carboxylate,

(+), (-), or(+/-)-3',3",4',4"Tetrahydrodispiro[cyclopentane-1,1'(2'H)-napthlene-2',2"(5"H)-furan]-5"-one,

(+), (-), or(+/-)-3',3",4',4"-Tetrahydro-7'-methoxydispiro[cyclopentane-1,1'(2'H)-napthlene-2',2"(5"H)-furan]-5"-one,

(+), (-), or(+/-)-3",4"-Dihydrodispiro[cyclopentane-1,1'-[1H]indene-2'(3'H),2"(5"H)-furan]-5"-one,

(+), (-), or(+/-)-3",4"-Dihydro-6'-methoxydispiro[cyclopentane-1,1'-[1H]indene-2'(3'H),2"(5"H)-furan]-5"-one,

(+), (-), or(+/-)-3',4'-Dihydro-2'-hydroxyspiro[cyclopentane-1,1'(2'H)-naphthalene]-2'-propanamide,

(+), (-), or(+/-)-3',4'-Dihydro-2'-hydroxy-7'methoxyspiro[cyclopentane-1,1'(2'H)-naphthalene]-2'propanamide,

(+), (-), or(+/-)-2',3'-Dihydro-2'-hydroxyspiro-[cyclopentane-1,1'-[1H]indene]-2'-propanamide,

(+), (-), or(+/-)-2',3'-Dihydro-2'-hydroxy-6'-methoxyspiro[cyclopentane-1,1'-[1H]indene]-2'-propanamide,

(+), (-), or(+/-)-2'-(3-aminopropyl)-3',4'dihydrospiro[cyclopentane-1,1'(2'H)napthalen]-2'-ol,

(+), (-), or(+/-)-2'-(3-aminopropyl)-3',4'-dihydro-7'-methoxyspiro[cyclopentane-1,1'(2'H)napthalen]2'-ol,

(+), (-), or(+/-)-2'-(3-aminopropyl)-2',3'-dihydrospiro[cyclopentane-1,1'-[1H]inden]-2'-ol,

(+), (-), or(+/-)-2'-(3-aminopropyl)-2',3'-dihydro-6'-methoxyspiro[cyclopentane-1,1'-[1H]inden]-2'-ol,

(+), (-), or(+/-)-2,2,2-Trichloroethyl-[3-(3',4'-dihydro-2'-hydroxyspiro[cyclopentane-1,1'(2'H)napthlene]-2'-yl)propyl]carbamate,

(+), (-), or(+/-)-2,2,2-Trichloroethyl-[3-(3',4'-dihydro-2'-hydroxy-7'-methoxyspiro[cyclopentane1,1'(2'H)-napthlene]-2'-yl)propyl]carbamate,

(+), (-), or(+/-)-2,2,2-Trichloroethyl-[3-(2',3'-dihydro-2'-hydroxyspiro[cyclopentane-1,1'-[1H]inden]-2'-yl)propyl]carbamate,

(+), (-), or(+/-)-2,2,2-Trichloroethyl-[3-(2',3'dihydro-2'-hydroxy-6'-methoxyspiro[cyclopentane-1,1'-[1H]inden]-2'-yl)-propyl]carbamate,

(+), (-), or(+/-)-2,2,2-Trichloroethyl-3,4,5,6-tetrahydro-4a,10b-butanobenz[h]quinoline-1(2H)-carboxylate,

(+), (-), or(+/-)-2,2,2-Trichloroethyl-3,4,5,6-tetrahydro-9-methoxy-4a,10b-butanobenz[h]quinoline-1(2H)-carboxylate,

(+), (-), or(+/-)-2,2,2-Trichloroethyl-3,4-dihydro-4a,9b-butano-5H-indeno[1,2-b]pyridine-1(2H)-carboxylate,and

(+), (-), or(+/-)-2,2,2-Trichloroethyl-3,4-dihydro-8-methoxy-4a,9b-butano-5H-indeno[1,2-b]pyridine-1(2H)-carboxylate.

The compounds of the instant invention exhibit valuable pharmacologicalproperties by selectively blocking the N-methyl-D-aspartate sensitiveexcitatory amino acid receptors in mammals. The compounds are thususeful for treating diseases responsive to excitatory amino acidblockade in mammals.

The effects are demonstrable in in vitro tests or in vivo animal testsusing mammals or tissues or enzyme preparations thereof, e.g., mice,rats, or monkeys. The compounds are administered enterally orparenterally, for example, orally, transdermally, subcutaneously,intravenously, or intraperitoneally. Forms include but are not limitedto gelatin capsules, or aqueous suspensions or solutions. The applied invivo dosage may range between about 0.01 to 100 mg/kg, preferablybetween about 0.05 and 50 mg/kg, most preferably between about 0.1 and10 mg/kg.

The ability of the compounds of the instant invention to interact withphencyclidine (PCP) receptors which represents a noncompetitive NMDAantagonist binding site, is shown by Examples 23 and 27 which bind withan affinity of less than 10 μM. Tritiated1-[1-(2-thienyl)cyclohexyl]pipiridine (TCP) binding, designated RBS1,was carried out essentially as described in J. Pharmacol. Exp. Ther.238, 739 (1986).

For medical use, the amount required of a compound of formula I orpharmacologically acceptable salt thereof--(hereinafter referred to asthe active ingredient) to achieve a therapeutic effect will, of course,vary both with the particular compound, the route of administration andthe mammal under treatment and the particular disorder or diseaseconcerned. A suitable systemic dose of a compound of formula I orpharmacologically acceptable salt thereof for a mammal suffering from,or likely to suffer from any condition as described herein before is inthe range 0.01 to 100 mg of base per kilogram body weight, the mostpreferred dosage being 0.05 to 50 mg/kg of mammal body weight.

It is understood that the ordinarily skilled physician or veterinarianwill readily determine and prescribe the effective amount of thecompound for prophylactic or therapeutic treatment of the condition forwhich treatment is administered. In so proceeding, the physician orveterinarian could employ an intravenous bolus followed by intravenousinfusion and repeated administrations, parenterally or orally, asconsidered appropriate.

While it is possible for an active ingredient to be administered alone,it is preferable to present it as a formulation.

Formulations of the present invention suitable for oral administrationmay be in the form of discrete units such as capsules, cachets, tablets,or lozenges, each containing a predetermined amount of the activeingredient; in the form of a powder or granules; in the form of asolution or a suspension in an aqueous liquid or nonaqueous liquid; orin the form of an oil-in-water emulsion or a water-in-oil emulsion. Theactive ingredient may also be in the form of a bolus, electuary, orpaste.

A tablet may be made by compressing or molding the active ingredientoptionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing, in a suitable machine, the activeingredient in a free-flowing form such as a powder or granules,optionally mixed with a binder, lubricant, inert diluent, surfaceactive, or dispersing agent. Molded tablets may be made by molding, in asuitable machine, a mixture of the powdered active ingredient and asuitable carrier moistened with an inert liquid diluent.

Formulations suitable for parenteral administration convenientlycomprise a sterile aqueous preparation of the active ingredient which ispreferable isotonic with the blood of the recipient.

Formulations suitable for nasal or buccal administration (such asself-propelling powder dispensing formulations described hereinafter),may comprise 0.1 to 20% w/w, for example, 2% w/w of active ingredient.

The formulations, for human medical use, of the present inventioncomprise an active ingredient in association with a pharmaceuticalyacceptable carrier therefor and optionally other therapeuticingredient(s). The carrier(s) must be `acceptable` in the sense of beingcompatible with the other ingredients of the formulations and notdeleterious to the recipient thereof.

So the pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions comprising an effectiveamount thereof in conjunction or admixture with excipients or carrierssuitable for either enteral or parenteral application. Preferred aretablets and gelatin capsules comprising the active ingredient togetherwith a) diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol,cellulose, and/or glycine; b) lubricants, e.g. silica, talcum, stearicacid, its magnesium or calcium salt, and/or polyethyleneglycol; fortablets also c) binders e.g. magnesium aluminum silicate, starch paste,gelatin, tragacanth, methylcellulose, sodium carboxymethylcelluloseand/or polyvinylpyrrolidone; if desired d) disintegrants, e.g. starches,agar, alginic acid, or its sodium salt, or effervescent mixtures; and/ore) absorbents, colorants, flavors, and sweeteners. Injectablecompositions are preferably aqueous isotonic solutions or suspensions,and suppositories are advantageously prepared from fatty emulsions, orsuspensions. Said compositions may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressure,and/or buffers. In addition, they may also contain other therapeuticallyvaluable substances. Said compositions are prepared according toconventional mixing, granulating, or coating methods, respectively, andcontain about 0.1 to 75%, preferably about 1 to 50%, of the activeingredient.

The formulations may conveniently be presented in unit dosage form andmay be prepared by any of the methods well-known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the formulations are prepared by uniformly andintimately bringing the active ingredient into association with a liquidcarrier or a finely divided solid carrier or both, and then, ifnecessary, shaping the product into the desired formulation.

The following examples are illustrative of the present invention but arenot intended to limit it in any way.

EXAMPLE 1 ##STR13##3',4'-Dihydrospiro[cyclopentane-1,1'(2'H)-napthlen]-2'-one

A suspension of KOt-Bu (76.3 g, 0.68 mol) in 500 mL of xylene wastreated dropwise with 2-tetralone (50 g, 0.34 mol). The resultingsolution was treated dropwise with 1,4-dibromobutane (74.0 g, 0.34 mol)(exothermic reaction). The resulting suspension was heated to reflux for18h. The reaction mixture was treated with water (200 mL) and theorganic phase was collected. The aqueous phase was extracted with ethylacetate (2×200 mL) and the combined organic extracts were dried (MgSO₄),filtered and concentrated. Distillation of the residue provided theproduct (65.6 g, 96%) as a colorless liquid.

EXAMPLE 2 ##STR14##3',4'-Dihydro-7'-methoxyspiro[cyclopentane-1,1'(2'H)-napthlen]-2'-one

In a manner similar to that described in Example 1,7-methoxy-2-tetralone (20.0 g, 0.113 mol) was converted to the titlecompound (10.3 g, 40%) as a colorless oil.

EXAMPLE 3 ##STR15## Spiro[cyclopentane-1,1'-[1H]inden]-2'(3'H)-one

In a manner similar to that described in Example 1, 2-indanone isconverted to the title compound.

EXAMPLE 4 ##STR16##6'-Methoxy-spiro[cyclopentane-1,1'-[1H]inden]-2'(3'H)-one

In a manner similar to that described in Example 1, 5-methoxy-2-indanoneis converted to the title compound.

EXAMPLE 5 ##STR17##(+/-)-3',4+-Dihydro-2+-hydroxyspirocyclopentane-1,1'(2'H)-napthalen]-2'-acetonitrile

A solution of acetonitrile (1.1 g, 27.5 mmol) in 100 mL of anhydroustetrahydrofuran (THF) was cooled to -78° C. and treated with lithiumdiisopropylamide (18 mL of a 1.5M solution in tetrahydrofuran). Theresulting suspension was stirred at -78° C. for 30 minutes and treateddropwise with a solution of the product from Example 1 (5.0 g, 24.9mmol) in 10 mL of anhydrous THF. The resulting solution was warmed toroom temperature and saturated aq. NH₄ Cl solution (15 mL) was added.The organic phase was collected and the aqueous phase was extracted withether (3×50 mL). The combined organic phases were dried (MgSO₄),filtered and concentrated. The solid which formed was suspended indiisopropyl ether and collected by suction filtration. The material wasdried under vacuum to give the title compound (4.14 g, 69%) as a whitesolid mp 165°-166° C.

Anal. (C₁₆ H₁₉ NO) Calc'd: C, 79.63; H, 7.94; N, 5.80. Found: C, 79.72;H, 7.86; N, 5.81.

EXAMPLE 6 ##STR18##(+/-)-3',4,-Dihydro-2'-hydroxy-7'-methoxyspiro[cyclopentane-1,1'(2'H)-napthalen]-2'-acetonitrile

In a manner similar to that described in Example 5, the product ofExample 2 (10.0 g, 43.4 mmol) was converted to the title compound (4.33g, 37%) as a tan solid mp 126°-127° C.

Anal. (C₁₇ H₂₁ NO₂) Calc'd: C, 75.25; H, 7.80; N, 5.16. Found: C, 75.36;H, 7.67; N, 4.94.

EXAMPLE 7 ##STR19##(+/-)-2',3'-Dihydro-2'-hydroxyspiro[cyclopentane-1,1'-[1H]inden]-2'-acetonitrile

In a manner similar to that described in Example 5, the product ofExample 3 is converted to the title compound.

EXAMPLE 8 ##STR20##(+/-)-2',3'-Dihydro-2'-hydroxy-6-methoxyspiro[cyclopentane-1,1'-[1H]inden]-2'-acetonitrile

In a manner similar to that described in Example 5, the product ofExample 4 is converted to the title compound.

EXAMPLE 9 ##STR21##(+/-)-2'-(2-Aminoethyl)-3',4'-dihydrospiro[cyclopentane-1,1'(2'H)-napthalen]-2'-ol

A solution of the product from Example 5 (2.50 g, 10.3 mmol) in 100 mLof methanolic ammonia was hydrogenated over Raney nickel (2.0 g) at 52psi for 7.5 hours. The reaction mixture was filtered to remove thecatalyst and the filtrate concentrated to give the title compound (2.59g, quantitative) as a pale green solid mp 107°-109° C.

Anal (C₁₆ H₂₃ NO) Calc'd: C, 79.63; H, 7.94; N, 5.81. Found: C, 79.37;H, 8.02; N, 5.59.

EXAMPLE 10 ##STR22##(+/-)-2'-(2-Aminoethyl)-3',4'-dihydro-7'-methoxyspiro[cyclopentane-1,1'(2'H)-napthalen]-2'-ol

In a manner similar to that described for Example 9, the product ofExample 6 (4.85 g, 17.9 mmol) was hydrogenated to give the titlecompound (4.86 g, 99%) as a pale green solid.

Anal. (C₁₇ H₂₅ NO₂) Calc'd: C, 74.14; H, 9.15; N, 5.08. Found: C, 73.40;H, 9.19; N, 5.04.

EXAMPLE 11 ##STR23##(+/-)-2'-(2-Aminoethyl)-2',3'-dihydrospiro[cyclopentane-1,1'-[1H]inden-2'-ol

In a manner similar to that described for Example 9, the product ofExample 7 is hydrogenated to give the title compound.

EXAMPLE 12 ##STR24##(+/-)-2'-(2-Aminoethyl)-2',3'-dihydro-6'-methoxyspiro[cyclopentane-1,1'-[1H]inden-2'-ol

In a manner similar to that described for Example 9, the product ofExample 8 is hydrogenated to give the title compound.

EXAMPLE 13 ##STR25## Ethyl(+/-)-[2-(3',4'-dihydro-2'-hydroxyspiro[cyclopentane-1,1'(2'H)-napthalen]-2'-yl)ethyl]carbamate

A solution of the product from Example 9 (1.05 g, 4.28 mmol) andtriethylamine (0.44 g, 4.35 mmol) in 10 mL of CH₂ Cl₂ was cooled to 0°C. and ethyl chloroformate (0.47 g, 4.33 mmol) in 5 mL CH₂ Cl₂ was addeddropwise. The reaction was warmed to room temperature and washed withwater. The aqueous phase was extracted with CH₂ Cl₂ (3×20 mL) and thecombined organic extracts were dried (MgSO₄), filtered and concentrated.The residue was purified by chromatography (silica gel, 1:1heptane/ethyl acetate) to give the title compound (1.33 g, 98%) as anoil.

EXAMPLE 14 ##STR26## 2,2,2-Trichloroethyl(+/-)-[2-(3',4'-dihydro-2'-hydroxyspiro[cyclopentane-1,1'(2'H)-naphthalen]-2'-yl)ethyl]carbamate

A solution of the product from Example 9 (0.88 g, 3.59 mmol) andtriethylamine (0.40 g, 3.78 mmol) in 10 mL of CH₂ Cl₂ was cooled to 0°C. and treated dropwise with 2,2,2-trichloroethylchloroformate (0.80 g,3.78 mmol) in 2 mL CH₂ Cl₂. The resulting solution was stirred at 0° C.for 30 minutes and warmed to room temperature. The reaction mixture waswashed with saturated aq. NaHCO₃ solution (10 mL). The aqueous phase wasextracted with CH₂ Cl₂ (10 mL). The combined organic extracts were dried(MgSO₄), filtered and concentrated. The residue was purified bychromatography (silica gel, 10:1 heptane/ethyl acetate) to give thetitle compound (1.18 g, 78%) as a viscous oil.

EXAMPLE 15 ##STR27## 2,2,2-Trichloroethyl(+/-)-[2-(3',4'-dihydro-2'-hydroxy-7'-methoxyspiro[cyclopentane-1,1'(2'H)-naphthalen]-2'-2'-yl)ethyl]carbamate

In a manner similar to that described in Example 14, the product ofExample 10 (4.66 g, 16.9 mmol) is converted to the title compound (6.81g, 89%) as a foamy white solid.

EXAMPLE 16 ##STR28## 2,2,2-Trichloroethyl(+/-)-[2-[2',3'-dihydro-2'-hydroxy-spiro[cyclopentane-1,1'-[1H]inden]-2'-yl)ethyl]carbamate

In a manner similar to that described in Example 14, the product ofExample 11 is converted to the title compound.

EXAMPLE 17 ##STR29## 2,2,2-Trichloroethyl(+/-)-2-[2',3'-dihydro-2'-hydroxy-6'-methoxyspiro[cyclopentane-1,1'-[1H]inden]-2'-yl)ethyl]carbamate

In a manner similar to that described in Example 14, the product ofExample 12 is converted to the title compound.

EXAMPLE 18 ##STR30## Ethyl(+/-)-2,3,4,5-tetrahydro-3a,9b-butano-1H-benz[q]indole-1-carboxylate

A solution of the product from Example 13 (1.68 g, 5.29 mmol) in 15 mLof 3:1 acetic acid/concentrated sulfuric acid (v/v) was stirred at roomtemperature for 18 hours. The reaction mixture was poured into water (50mL) and the resulting mixture was extracted with CH₂ Cl₂ (4×30 mL). Thecombined organic extracts were dried (MgSO₄), filtered and concentrated.The residue was dissolved in CH₂ Cl₂ (100 mL) and washed with saturatedaq. bicarbonate solution (30 mL). The organic phase was dried (MgSPO₄),filtered and concentrated. The residue was purified by chromatography(silica gel, 9:1 heptane/ethyl acetate) to give the title compound (0.94g, 59%) as a white solid mp 67°-69° C.

Anal. (C₁₉ H₂₅ NO₂) Calc'd: C, 76.22; H, 8.42; N, 4.68. Found: C, 75.99;H, 8.38; N, 4.41.

EXAMPLE 19 ##STR31## 0 2,2,2-Trichloroethyl(+/-)-2,3,4,5-tetrahydro-3a,9b-butano-1H-benz[q]indole-1-carboxylate

In a manner similar to that described in Example 18, the product ofExample 14 (0.98 g, 2.33 mmol) was converted to the title compound (0.71g, 76%) as an oil.

EXAMPLE 20 ##STR32## 2,2,2-Trichloroethyl(+/-)-2,3,4,5-tetrahydro-8-methoxy-3a,9b-butano-1H-benz[q]indole-1-carboxylate

In a manner similar to that described in Example 18, the product ofExample 15 (5.16 g, 11.4 mmol) was converted to the title compound (4.18g, 84%) as an oil.

EXAMPLE 21 ##STR33## 2,2,2-Trichloroethyl(+/-)-2,3-dihydro-1H,4H-3a,8b-butanoindeno[1,2-b]pyrrole-1-carboxylate

In a manner similar to that described in Example 18, the product ofExample 16 is converted to the title compound.

EXAMPLE 22 ##STR34## 2,2,2-Trichloroethyl(+/-)-2,3-dihydro-7-methoxy-1H,4H-3a,8b-butanoindeno[1,2-b]pyrrole-1-carboxylate

In a manner similar to that described in Example 18, the product ofExample 17 is converted to the title compound.

EXAMPLE 23 ##STR35##(+/-)-2,3,4,5-Tetrahydro-3a,9b-butano-1H-benz[q]indole hydrochloride

A solution of the product from Example 19 (0.70 g, 1.74 mmol) in 20 mLof methanol and 0.5 mL acetic acid was treated with zinc dust (1.58 g,320 mesh) and the resulting suspension stirred at room temperature forthree hours. The reaction mixture was filtered and the filtrateconcentrated. The residue was dissolved in ether (30 mL) and extractedwith aqueous 1N HCl (3×15 mL). The combined acid extracts are made basic(pH=11) with potassium carbonate and the resulting aqueous solution wasextracted with CH₂ Cl₂ (5×15 mL). The combined organic extracts weredried (Na₂ SO₄), filtered and concentrated. The residue (0.30 g) wasconverted to its HCl salt by dissolution in ether and treatment with asaturated solution of HCl (gas) in ether. The solid which formed wascollected by filtration and dried under vacuum (100° C.) to give thetitle compound (0.25 g, 54%) as a white solid mp >270° C.

Anal (C₁₆ H₁₉ N.HCl) Calc'd: C, 72.85; H, 8.40; N, 5.31; Cl, 13.44.Found: C, 72.66; H, 8.38, N, 4.98; Cl, 13.83.

EXAMPLE 24 ##STR36##(+/-)-2,3,4,5-Tetrahydro-8-methoxy-3a,9b-butano-1H-benz]q]indole

In a manner similar to that described in Example 23, the product ofExample 20 (3.76 g, 8.67 mmol) was converted to the title compound 1.47g, 70%) as an oil. An analytical sample was prepared by crystallizationof the fumarate salt from acetone which gave a white solid mp 203°-204°C.

Anal. (C₁₇ H₂₃ NO.C₄ H₄ O₄) Calc'd: C, 67.54; H, 7.29; N, 3.75. Found:C, 67.55; H, 7.18; N, 3.61.

EXAMPLE 25 ##STR37##(+/-)-2,3-Dihydro-1H,4H-3a,8b-butanoindeno[1,2-b]pyrrole

In a manner similar to that described in Example 23, the product ofExample 21 is converted to the title compound.

EXAMPLE 26 ##STR38##(+/-)-2,3-Dihydro-7-methoxy-1H,4H-3a,8b-butanoindeno[1,2-b]pyrrole

In a manner similar to that described in Example 23, the product ofExample 22 is converted to the title compound.

EXAMPLE 27 ##STR39##(+/-)-2,3,4,5-Tetrahydro-1-methyl-3a,9b-butano-1H-benz[q]indolehydrochloride

A solution of the product from Example 18 (0.77 g, 2.56 mmol) in 5 mL ofTHF was added dropwise to a suspension of lithium aluminum hydride (0.76g, 20.0 mmol) in 15 mL of THF. The reaction mixture was stirred at roomtemperature for 18 hours and then heated to reflux for 1 hour. Thereaction mixture was cooled to room temperature and quenched by theaddition of small portions of Na₂ SO₄ -10H₂ O until no further gasevolution was observed. The reaction mixture was filtered and thefiltrate was concentrated. The residue was dissolved in ether andtreated with a saturated solution of dry HCl in ether. The solid whichformed was collected by suction filtration and dried under vacuum (100°C.) to give the product (0.51 g, 72%) as a white solid mp 241°-253° C.

Anal. (C₁₇ H₂₃ N.HCl) Calc'd: C, 73.49; H, 8.71; N, 5.04; Cl, 12.76 .Found: C, 73.39; H, 8.73; N, 4.82; Cl, 13.16.

EXAMPLE 28 ##STR40##(+/-)-2,3,4,5-Tetrahydro-8-methoxy-1methyl-3a,9b-butano-1H-benz[q]indole

A solution of the product from Example 24 (0.79 g, 3.08 mmol) and sodiumcyanoborohydride (0.80 g, 12.7 mmol) in 10 mL methanol was treateddropwise with a 37% aqueous formalin solution (5 mL). The resultingsolution was stirred at room temperature for 30 minutes, concentrated,and partitioned between 1N HCl (20 mL) and ether (20 mL). The organicphase was extracted with 1N HCl (2×10 mL) and the combined aqueousextracts were washed with ether. The aqueous phase was made basic withK₂ CO₃ and extracted with CH₂ Cl₂ (3×20 mL). The combined organicextracts were dried K₂ CO₃, filtered and concentrated to give the titlecompound (0.87 g, quantitative) as a white solid mp 100°-102° C.

Anal. (C₁₈ H₂₅ NO) Calc'd: C, 79.66; H, 9.29; N, 5.16. Found: C, 79.52;H, 9.53; N, 4.71.

EXAMPLE 29 ##STR41##(+/-)-2,3-Dihydro-1-methyl-1H,4H-3a,8b-butanoindeno[1,2-b]pyrrole

In a manner similar to that described in Example 28, the product ofExample 25 is converted to the title compound.

EXAMPLE 30 ##STR42##(+/-)-2,3-Dihydro-7-methoxy-1-methyl-1H,4H-3a,8b-butanoindeno[1,2-b)pyrrole

In a manner similar to that described in Example 28, the product ofExample 26 is converted to the title compound.

EXAMPLE 31 ##STR43##(+/-)-2,3,4,5-Tetrahydro-1-ethyl-3a,9b-butano-1-benz[q]indole fumarate

In a manner similar to that described in Example 28, the product fromExample 23 (0.30 g, 1.32 mmol) and sodium cyanoborohydride (0.30 g, 4.77mmol) was treated dropwise with acetaldehyde (0.20 g, 4.10 mmol) in 5 mLof methanol. Workup followed by crystallization of the fumarate saltfrom acetone gave the title compound (0.32 g, 65%) as a white solid mp172°-173° C.

Anal. (C₁₈ H₂₅ N.C₄ H₄ O₄) Calc'd: C, 71.13; H, 7.87; N, 3.77. Found: C,70.90: H, 7.79; N, 3.75.

EXAMPLE 32 ##STR44##(+/-)-2,3,4,5-Tetrahydro-8-methoxy-1-ethyl-3a,9b-butano-1H-benz[q]indolehydrobromide

In a manner similar to that described in Example 31, the product ofExample 24 (0.27 g, 1.13 mmol) and acetaldehyde (0.32 g, 7.12 mmol) arereacted. Workup, followed by crystallization from ether and HBr gave thetitle compound (0.27 g, 64%) as a white solid mp 248°-251° C.

Anal. (C₁₉ H₂₇ NO.HBr) Calc'd: C, 62.29; H, 7.71; N, 3.82; Br, 21.81.Found: C, 62.39; H, 7.65; N, 3.77; Br, 21.98.

EXAMPLE 33 ##STR45##(+/-)-2,3,4,5-Tetrahydro-1-propyl-3a,9b-butano-1H-benz[q]indolehydrobromide

In a manner similar to that described in Example 32, the product fromExample 23 (0.25 g, 1.10 mmol) and propionaldehyde (0.20 g, 3.47 mmol)was converted to the title compound (0.23 g, 60%) as a white solid mp196°-198° C.

Anal. (C₁₉ H₂₇ N.HBr) Calc'd: C, 64.92; H, 8.13; N, 4.07; Br, 23.09.Found: C, 65.14; H, 8.06; N, 4.00; Br, 22.80.

EXAMPLE 34 ##STR46##(+/-)-2,3,4,5-tetrahydro-1-(cyclopropylmethyl)-3a,9b-butano-1H-benz[q]indole fumarate

In a manner similar to that described in Example 31, the product fromExample 23 (0.25 g, 1.10 mmol) and cyclopropanecarboxaldehyde (0.23 g,1.10 mmol) was converted to the title compound (0.26 g, 58%) as a whitesolid mp 150°-152° C.

Anal. (C₂₀ H₂₇ N.1.2C₄ H₄ O₄) Calc'd: C, 70.80; H, 7.62; N, 3.33. Found:C, 71.05; H, 7.67, N, 3.32.

EXAMPLE 35 ##STR47##(+/-)-2,3,4,5-tetrahydro-1-phenylmethyl-3a,9b-butano-1H-benz[q]indolehydrochloride

In a manner similar to that described in Example 32, the product fromExample 23 (0.34 g, 1.50 mmol) and benzaldehyde are reacted. Workup,followed crystallization from ether and HCl gave the title compound(0.22 g, 42%) as a white solid mp 235°-237° C.

Anal. (C₂₃ H₂₇ N.HCl) Calc'd C, 78.05; H, 7.98; N, 3.96; Cl, 10.02.Found: C, 77.60; H, 8.00, N, 3.34; Cl, 10.24.

EXAMPLE 36 ##STR48##(+/-)-2,3,4,5-Tetrahydro-1-(2-propenyl)-3a,9b-butano-1H-benz[q]indole

In a manner similar to that described in Example 32, the product fromExample 23 is converted to the title compound.

EXAMPLE 37 ##STR49##(+/-)-2,3,4,5-Tetrahydro-3a,9b-butano-1H-benz[q]indol-8-ol

A solution of the product from Example 24 is heated to reflux in 48%aqueous HBr until the starting material is consumed. The reactionmixture is poured into cold NH₄ OH solution and extracted into ethylacetate. The combined organic extracts are dried (Na₂ SO₄) andconcentrated to give the title compound.

EXAMPLE 38 ##STR50##(+/-)-2,3,4,5-Tetrahydro-1-methyl-3a,9b-butano-1H-benz[q]indol-8-ol

In a manner similar to that described in Example 37, the product fromExample 28 is converted to the title compound.

EXAMPLE 39 ##STR51##(+/-)-2,3-Dihydro-1H,4H-3a,8b-butanoindeno[1,2-b]pyrrol-7-ol In a mannersimilar to that described in Example 37, the product from Example 26 isconverted to the title compound. EXAMPLE 40 ##STR52##(+/-)-2,3-Dihydro-1-methyl-1H,4H-3a,8b-butanoindeno[1,2-b]-pyrrol-7-ol

In a manner similar to that described in Example 37, the product fromExample 30 is converted to the title compound.

EXAMPLE 41 ##STR53##3',3",4',4"-Tetrahydrodispiro[cyclopentane-1,1'(2'H)-napthlene-2',2"(5"H)-furan]-5"-one

A solution of triethylsilyl N,N,N',N'-tetramethyl phosphoramidate (J.Amer. Chem. Soc. 1978, 100, 3468) (1.1 eq.) in anhydrous ether is cooledto 0° C. and treated with acrolein (1.0 eq.) in anhydrous ether. Theresulting solution is stirred at 0° C. for 4.5 hours then cooled to -78°C. and a solution of n-butyllithium (1.0 eq.) is added. The resultingsolution is treated with the product from Example 1 (1.0 eq.) andstirred at -78° C. for several hours. The reaction mixture is quenchedwith brine and extracted with several portions of ether. The combinedextracts are dried and concentrated. The residue is dissolved in THF andcooled to 0° C. and tetra-n-butylammonium flouride (5 eq.) is added. Thereaction mixture is warmed to room temperature and worked up as above togive the title compound.

EXAMPLE 42 ##STR54##3',3",4',4"-Tetrahydro-7'-methoxydispiro[cyclopentane-1,1'(2'H)-napthlene-2',2"(5"H)furan]-5"-one

In a manner similar to that described in Example 41, the product fromExample 2 is converted to the title compound.

EXAMPLE 43 ##STR55##3",4"-Dihydrodispiro[cyclopentane-1,1'-[1H]indene-2'(3'H),2"(5"H)-furan]-5"-one

In a manner similar to that described in Example 41, the product fromExample 3 is converted to the title compound.

EXAMPLE 44 ##STR56##3",4"-Dihydro-6'-methoxydispiro[cyclopentane-1,1'-[1H]indene-2'(3'H),2"(5"H)-furan]-5"-one

In a manner similar to that described in Example 41, the product fromExample 4 is converted to the title compound.

EXAMPLE 45 ##STR57##(+/-)-3',4'-Dihydro-2'-hydroxyspiro[cyclopentane-1,1'(2'H)-naphthalene]-2'-propanamide

A solution of the product from Example 41 is placed in a high pressurereactor and dissolved in tetrahydrofuran. Ammonia is condensed into thesolution and the reaction vessel is sealed and the reaction mixture isstirred at room temperature for approximately 24 hours. The reactionvessel is vented and the remaining solvent is concentrated to give thetitle compound.

EXAMPLE 46 ##STR58##

(+/-)-3',4'-Dihydro-2'-hydroxy-7'-methoxyspiro[cyclopentane-1,1'(2'H)-naphthalene]-2'-propanamide

In a manner similar to that described in Example 45, the product fromExample 42 is converted to the title compound.

EXAMPLE 47 ##STR59##(+/-)-2',3'-Dihydro-2,-hydroxyspiro[cyclopentane-1,1'-[1H]indene]-2,-propanamide

In a manner similar to that described in Example 45, the product fromExample 43 is converted to the title compound.

EXAMPLE 48 ##STR60##(+/-)-2',3'-Dihydro-2'-hydroxy-6'-methoxyspiro[cyclopentane-1,1'-[1H]indene]-2'-propanamide

In a manner similar to that described in Example 45, the product fromExample 44 is converted to the title compound.

EXAMPLE 49 ##STR61##(+/-)-2'-(3-Aminopropyl)-3',4'-dihydrospiro[cyclopentane-1,1'(2'H)napthalen]-2'-ol

A solution of the product from Example 45, in tetrahydrofuran (THF) isadded dropwise to a suspension of lithium aluminumhydride in THF. Theresulting suspension is heated to reflux for 1 hour and then stirred atroom temperature for 18 hours. The reaction mixture is quenched by theaddition of small portions of Na₂ SO₄ -10H₂ O until no more gasevolution is observed. The resulting suspension is filtered and thefiltrate is concentrated to give the title compound.

EXAMPLE 50 ##STR62##(+/-)-2'-(3-Aminopropyl)-3',4'-dihydro-7'-methoxyspiro[cyclopentane-1,1'(2'H)napthalen]-2'-ol

In a manner similar to that described in Example 49, the product fromExample 46 is converted to the title compound.

EXAMPLE 51 ##STR63##(+/-)-2'-(3-Aminopropyl)-2',3'-dihydrospiro[cyclopentane-1,1'-[1H]inden]-2'-ol

In a manner similar to that described in Example 49, the product fromExample 47 is converted to the title compound.

EXAMPLE 52 ##STR64##(+/-)-2'-(3-Aminopropyl)-2',3'-dihydro-6'-methoxyspiro[[cyclopentane-1,1'(2'H)-napthlene]-2'-yl)propyl]carbamate

In a manner similar to that described in Example 49, the product fromExample 48 is converted to the title compound.

EXAMPLE 53 ##STR65## 2,2,2-Trichloroethyl(+/-)-3-(3',4'-dihydro-2'-hydroxyspiro[cyclopentane-1,1'(2'H)-napthlene]-2'-yl)propyl]carbamate

A solution of the product from Example 49 (1.0 eq.) and triethylamine(1.1 eq.) in CH₂ Cl₂ is cooled to 0° C. and a solution of2,2,2-trichloroethylchloroformate (1.1 eq.) in CH₂ Cl₂ is addeddropwise. The resulting solution is stirred at 0° C. for 30 minutes andwarmed to room temperature. The reaction mixture is washed withbicarbonate, dried and concentrated to give the title compound.

EXAMPLE 54 ##STR66## 2,2,2-Trichloroethyl(+/-)-[3-(3',4'-dihydro-2'-hydroxy-7'-methoxyspiro[cyclopentane-1,1'(2'H)-napthlene]-2'-yl)propyl]carbamate

In a manner similar to that described in Example 53, the product fromExample 50 is converted to the title compound.

EXAMPLE 55 ##STR67## 2,2,2-Trichloroethyl(+/-)-[3-(2',3'-dihydro-2'-hydroxyspiro[cyclopentane-1,1'[1H]inden]-2'-yl)propyl]carbamate

In a manner similar to that described in Example 53, the product fromExample 51 is converted to the title compound.

EXAMPLE 56 ##STR68## 2,2,2-Trichloroethyl(+/-)-[3-(2',3'-dihydro-2'-hydroxy-6'-methoxyspiro[cyclopentane-1,1'[1H]inden]-2'-yl)propyl]carbamate

In a manner similar to that described in Example 53, the product fromExample 52 is converted to the title compound.

EXAMPLE 57 ##STR69## 2,2,2-Trichloroethyl(+/-)-3,4,5,6-tetrahydro-4a,10b-butanobenz[h]quinoline-1(2H)-carboxylate

In a manner similar to that described in Example 18, the product fromExample 53 is converted to the title compound.

EXAMPLE 58 ##STR70## 2,2,2-Trichloroethyl(+/-)-3,4,5,6-tetrahydro-9-4a,10b-butanobenz[h]quinoline-1(2H)-carboxylate

In a manner similar to that described in Example 18, the product fromExample 54 is converted to the title compound.

EXAMPLE 59 ##STR71## 2,2,2-Trichloroethyl(+/-)-3,4-dihydro-4a,9b-butano-5H-indeno[1,2-b]pyridine-1(2H)-carboxylate

In a manner similar to that described in Example 18, the product fromExample 55 is converted to the title compound.

EXAMPLE 60 ##STR72## 2,2,2-Trichloroethyl(+/-)-3,4-dihydro-8-methoxy-4a,9b-butano-5H-indeno[1,2-b]pyridine-1(2H)-carboxylate

In a manner similar to that described in Example 18, the product fromExample 56 is converted to the title compound.

EXAMPLE 61 ##STR73##(+/-)-1,2,3,4,5,6-Hexahydro-4a,10b-butanobenz[h]quinoline

In a manner similar to that described in Example 23, the product fromExample 57 is converted to the title compound.

EXAMPLE 62 ##STR74##(+/-)-1,2,3,4,5,6-Hexahydro-9-methoxy-4a,10b-butanobenz[h]-quinoline

In a manner similar to that described in Example 23, the product fromExample 58 is converted to the title compound.

EXAMPLE 63 ##STR75##(+/-)-1,2,3,4-Tetrahydro-4a,9b-butano-5H-indeno[1,2-b]pyridine

In a manner similar to that described in Example 23, the product fromExample 59 is converted to the title compound.

EXAMPLE 64 ##STR76##(+/-)-1,2,3,4-Tetrahydro-8-methoxy-4a,9b-butano-5H-indeno[1,2-b]pyridine

In a manner similar to that described in Example 23, the product fromExample 60 is converted to the title compound.

EXAMPLE 65 ##STR77##(+/-)-1,2,3,4,5,6-Hexahydro-1-methyl-4a,10b-butanobenz[h]quinoline

In a manner similar to that described in Example 28, the product fromExample 61 is converted to the title compound.

EXAMPLE 66 ##STR78##(+/--)-1,2,3,4,5,6-Hexahydro-9-methoxy-1-methyl-4a,10b-butanobenz[h]quinoline

In a manner similar to that described in Example 28, the product fromExample 62 is converted to the title compound.

EXAMPLE 67 ##STR79##(+/-)-1,2,3,4-Tetrahydro-1-methyl-4a,9b-butano-5H-indeno[1,2-b]pyridine

In a manner similar to that described in Example 28, the product fromExample 63 is converted to the title compound.

EXAMPLE 68 ##STR80##(+/-)-1,2,3,4-Tetrahydro-8-methoxy-1-methyl-4a,9b-butano-5H-indeno[1,2-b]pyridine

In a manner similar to that described in Example 28, the product fromExample 64 is converted to the title compound.

EXAMPLE 69 ##STR81##(+/-)-1,2,3,4,5,6-Hexahydro-4a,10b-butanobenz[h]quinoline-9-ol

In a manner similar to that described in Example 37, the product fromExample 62 is converted to the title compound.

EXAMPLE 70 ##STR82##(+/-)-1,2,3,4,5,6-Hexahydro-1-methyl-4a,10b-butanobenz[h]quinoline-9-ol

In a manner similar to that described in Example 37, the product fromExample 64 is converted to the title compound.

EXAMPLE 71 ##STR83##(+/-)-1,2,3,4-Tetrahydro-4a,9b-butano-5H-indeno[1,2-b]pyridin-8-ol

In a manner similar to that described in Example 37, the product fromExample 66 is converted to the title compound.

EXAMPLE 72 ##STR84##(+/-)-1,2,3,4-Tetrahydro-1-methyl-4a,9b-butano-5H-indeno[1,2-b]pyridin-8-ol

In a manner similar to that described in Example 37, the product fromExample 68 is converted to the title compound.

I claim:
 1. A process for the preparation of a compound of formula:##STR85## or a pharmaceutically acceptable acid addition salt thereofwherein: R¹ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl,arylloweralkyl, cyclopropylloweralkyl;R² and R³ are each independentlyhydrogen, lower alkyl, hydroxy, lower alkoxy, halogen, amino,monoloweralkyamino or diloweralkylamino; m is an integer of from 0 to 2; and n is an integer of from 2 to 4; consisting essentially of:(a)reacting a compound of formula III ##STR86## with lithioacetonitrile ina solvent at a temperature of from about -78° C. to about 20° C. toproduce a compound of formula IV: ##STR87## (b) hydrogenatingcatalytically a compound from step (a) a solvent under a hydrogenatmosphere to produce a compound of formula V wherein n is 2; ##STR88##(c) reacting a compound from step (b) with an alkylchloroformate in thepresence of trialkylamine in a solvent to produce a compound of formulaIX, wherein R⁵ is an acid stable protecting group selected from methyl,ethyl, 2,2,2-trichloroethyl, (-)-methanol, or (-)-α-methylbenzyl;##STR89## (d) reacting a compound from step (c) with an acid to producea compound of formula X; and ##STR90## (e) reacting a compound from step(d) to remove the carbamate functionality with zinc dust in alcohol inthe presence of a weak acid to produce the desired compound of formula Iand ##STR91## isolating or converting to a pharmaceutically acceptablesalt thereof.
 2. A process according to claim 1 wherein in step (e) acompound from step (d) is reduced in the presence of lithium aluminumhydride or diborane in a solvent selected from ether and tetrahydrofuranto produce a compound of formula I wherein R is methyl, and isolating orconverting to a pharmaceutically acceptable salt thereof.
 3. A processfor the preparation of a compound of formula V consisting essentiallyof: ##STR92## (a) reacting a compound of formula III ##STR93## with acompound of formula VI ##STR94## to produce a compound of formula VII##STR95## (b) reacting a compound produced in step (a) with ammonia in asolvent to produce a compound of formula VIII ##STR96## (c) reacting acompound from step (b) with a reducing agent in a solvent to produce thecompound of formula V wherein n is 3.